Compounds useful as inhibitors of ATR kinase

Abstract

The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and solid forms of the compounds of this invention. The compounds of this invention have formula I-A or I-B: wherein the variables are as defined herein.

We claim: 
     
       1. A process for preparing a compound of formula I-1: 
       
         
           
           
               
               
           
         
         comprising the steps of: 
         a) reacting a compound of formula 6a*: 
       
       
         
           
           
               
               
           
         
         with a compound of formula 27: 
       
       
         
           
           
               
               
           
         
         under suitable amide bond formation conditions to form a compound of formula 28: 
       
       
         
           
           
               
               
           
         
         b) purifying the compound of formula 28 using a suitable palladium sequestering agent; 
         c) reacting the compound of formula 28 under suitable deprotection conditions to form a compound of formula 30 
       
       
         
           
           
               
               
           
         
         d) reacting the compound of formula 30 with a compound of formula 25: 
       
       
         
           
           
               
               
           
         
         under suitable amide bond formation conditions to form the compound of formula I-1. 
       
     
     
       2. The process of  claim 1 , wherein suitable conditions for forming the amide bond comprise reacting the compound of formula 30 with the compound of formula 25 in the presence of an amide coupling partner, an aprotic solvent, and a base. 
     
     
       3. The process of  claim 2 , wherein the aprotic solvent is independently selected from N-Methyl-2-Pyrrolidone (NMP), dimethylformamide (DMF), or tetrahydrofuran. 
     
     
       4. The process of  claim 3 , wherein the aprotic solvent is tetrahydrofuran. 
     
     
       5. The process of  claim 2 , wherein the base is an aliphatic amine. 
     
     
       6. The process of  claim 5 , wherein the base is diisopropylethylamine (DIPEA). 
     
     
       7. The process of  claim 2 , wherein the amide coupling partner is independently selected from 1,1′-Carbonyldiimidazole (CDI), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), or O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU). 
     
     
       8. The process of  claim 7 , wherein the amide coupling partner is O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU). 
     
     
       9. The process of  claim 7 , wherein the amide coupling partner is 1,1′-Carbonyldiimidazole (CDI). 
     
     
       10. The process of  claim 1 , wherein suitable deprotection conditions comprise reacting the compound of formula 28 with an acid in the presence of a solvent. 
     
     
       11. The process of  claim 10 , wherein the acid is HCl. 
     
     
       12. The process of  claim 10 , wherein the solvent is 1,4-dioxane. 
     
     
       13. The process of  claim 1 , wherein the suitable conditions for forming the amide bond comprise reacting the compound of formula 6a* with the compound of formula 27 in an aprotic solvent under heat. 
     
     
       14. The process of  claim 13 , wherein the aprotic solvent is independently selected from N-Methyl-2-Pyrrolidone (NMP), pyridine, or dimethylformamide (DMF). 
     
     
       15. The process of  claim 14 , wherein the aprotic solvent is pyridine. 
     
     
       16. The process of  claim 15 , wherein the reaction is carried out at a temperature of at least 80° C. 
     
     
       17. The process of  claim 1 , wherein the palladium scavenger is independently selected from propane-1,2-diamine, ethane-1,2-diamine, ethane-1,2-diamine, propane-1,3-diamine, tetramethylethelenediamine, ethylene glycol, 1,3-bis(diphenylphosphanyl)propane, 1,4-bis(diphenylphosphanyl)butane, and 1,2-bi s(diphenylphosphanyl)ethane/Pr-1,2-diamine. 
     
     
       18. The process of  claim 17 , wherein the palladium scavenger is propane-1,2-diamine.